Tovorafenib

Acknowledgment
This article consists of drug labeling information developed under U.S. FDA guidance and excerpted from DailyMed. It was not reviewed by the MedLink Neurology Editorial Board. For the latest FDA-approved information about this drug, visit Drugs@FDA.com.

Highlights

Indications and usage
Tovorafenib (Ojemda™) is a kinase inhibitor indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent on verification and description of clinical benefit in a confirmatory trial(s).
Dosage and administration
	• Confirm the presence of BRAF fusion or rearrangement, or BRAF V600 mutation before initiation of treatment with tovorafenib.
	• Recommended dosage of tovorafenib is based on body surface area.
	• Administer tovorafenib orally, once weekly, with or without food.
	• Tablets. Swallow tablets whole with water. Do not chew, cut, or crush.
	• For oral suspension. See full prescribing information for preparation and administration instructions.
Dosage forms and strengths
Tablets: 100 mg For oral suspension: 25 mg/mL
Note: Tovorafenib was first approved by the U.S. FDA in 2024.

Contraindications
None.
Warnings and precautions
	• Hemorrhage. Major hemorrhagic events can occur during treatment with tovorafenib. Withhold, resume at reduced dose, or permanently discontinue based on severity.
	• Skin toxicity, including photosensitivity. Advise patients to monitor for new or worsening skin reactions. Advise patients to limit direct ultraviolet exposure and use precautionary measures such as sunscreen, sunglasses, or protective clothing during treatment with tovorafenib. Withhold, reduce the dose, or permanently discontinue based on severity.
	• Hepatotoxicity. Tovorafenib can cause hepatotoxicity. Monitor liver function tests before administration and during treatment. Withhold, reduce the dose, or permanently discontinue based on severity.
	• Effect on growth. Reductions in growth velocity have been reported. Routinely monitor growth in pediatric patients.
	• Embryo-fetal toxicity. Can cause fetal harm. Advise of the potential risk to a fetus and to use effective nonhormonal contraception.
	• Neurofibromatosis type 1-associated tumors. Increased tumor growth may occur with tovorafenib.
Adverse reactions
The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.
To report suspected adverse reactions, contact Day One Biopharmaceuticals at 1-877-204-2820 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See Patient counseling information and medication guide available in the DAILYMED drug label information.
Drug interactions
	• Moderate and strong CYP2C8 inhibitors. Avoid coadministration with tovorafenib.
	• Moderate and strong CYP2C8 inducers. Avoid coadministration with tovorafenib.
	• Certain CYP3A substrates. Avoid coadministration of tovorafenib with CYP3A substrates where minimal concentration changes can cause reduced efficacy.
	• Hormonal contraceptives. Avoid coadministration with tovorafenib.
Use in specific populations
	• Lactation. Advise not to breastfeed.
	• Infertility. May impair fertility in males and females.

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Tovorafenib is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.

This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory trials.

Dosage and administration

Patient selection

Select patients for treatment with tovorafenib based on the presence of BRAF fusion or rearrangement, or BRAF V600 mutation in tumor specimens.

Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics.

Recommended testing before initiating tovorafenib

Before initiating tovorafenib, evaluate liver function tests, including ALT, AST, and bilirubin.

Recommended dosage

The recommended dosage of tovorafenib based on body surface area is 380 mg/m² orally once weekly (the maximum recommended dosage is 600 mg orally once weekly) with or without food until disease progression or intolerable toxicity. Tovorafenib may be administered as an immediate-release tablet (see Table 1) or as an oral suspension (see Table 2). A recommended dosage for patients with a body surface area less than 0.3 m² has not been established.

Table 1. Recommended Tovorafenib Tablets Dosage Based on Body Surface Area

Body surface area (m²)	Recommended dosage
0.30-0.89	Administer tovorafenib oral suspension once weekly (see Table 2)
0.90-1.12	400 mg once weekly
1.13-1.39	500 mg once weekly
≥ 1.40	600 mg once weekly

Table 2. Recommended Dosage for Tovorafenib for Oral Suspension Based on Body Surface Area

Body surface area (m²)	Dose volume (mL)*	Dosage
0.30-0.35	5	125 mg once weekly
0.36-0.42	6	150 mg once weekly
0.43-0.48	7	175 mg once weekly
0.49-0.54	8	200 mg once weekly
0.55-0.63	9	225 mg once weekly
0.64-0.77	11	275 mg once weekly
0.78-0.83	12	300 mg once weekly
0.84-0.89	14	350 mg once weekly
0.90-1.05	15	375 mg once weekly
1.06-1.25	18	450 mg once weekly
1.26-1.39	21	525 mg once weekly
≥1.40	24	600 mg once weekly
* Tovorafenib for oral suspension has a concentration of 25 mg/mL. Each bottle of tovorafenib for oral suspension delivers 300 mg/12 mL.

Continue once weekly dosing until disease progression or intolerable toxicity.

Administration

	• Take tovorafenib at a regularly scheduled time once weekly.
	• Tovorafenib may be taken with or without food.

If a dose is missed by:

	• Three days or less, take the missed dose as soon as possible, and take the next dose on its regularly scheduled day.
	• More than 3 days, skip the missed dose and take the next dose on its regularly scheduled day.

If vomiting occurs immediately after taking a dose, repeat that dose.

Tovorafenib tablets.

	• Swallow tablets whole with water.
	• Do not chew, cut, or crush.

Tovorafenib for oral suspension.

Before first-time use of tovorafenib for oral suspension, ensure that caregivers (and if appropriate, patients) read and understand the "Instructions for Use" before preparing, measuring, and administering tovorafenib.

Preparation and administration.

	• Reconstitute the powder in each supplied bottle with exactly 14 mL of room temperature water to form the tovorafenib for oral suspension. After reconstitution, each mL contains 25 mg of tovorafenib. Product foaming after reconstitution reduces the deliverable volume.
	• Each bottle delivers 300 mg of tovorafenib in 12 mL. For doses greater than 300 mg, reconstitute two bottles to achieve the dose. Split the dose as equally as possible between the two bottles (e.g., 6 mL and 7 mL for a 325 mg dose).
	• Administer tovorafenib for oral suspension using the supplied oral dosing syringe or feeding tube (minimum 12 French) immediately after preparation.
	• If the tovorafenib for oral suspension is not administered within 15 minutes after preparation, instruct the patient to discard it.

Dosage modifications for adverse reactions

The recommended dosage reductions for adverse reactions for tovorafenib tablets are provided in Table 3 and tovorafenib for oral suspension in Table 4.

Table 3. Tovorafenib Tablets: Recommended Dosage Reductions for Adverse Reactions

BSA (m²)	First dosage reduction	Second dosage reduction
0.30-1.12	Administer the oral suspension once weekly (see Table 4)
1.13-1.39	400 mg once weekly	Administer tovorafenib oral suspension once weekly (see Table 4)
≥1.40	500 mg once weekly	400 mg once weekly

Table 4. Tovorafenib for Oral Suspension: Recommended Dosage Reductions for Adverse Reactions

BSA (m²)	First dosage reduction		Second dosage reduction
	Volume (mL)	Dose (mg)	Volume (mL)	Dose (mg)
0.30-0.35	4	100 mg once weekly	3	75 mg once weekly
0.36-0.42	5	125 mg once weekly	4	100 mg once weekly
0.43-0.48	6	150 mg once weekly	5	125 mg once weekly
0.49-0.54	7	175 mg once weekly	6	150 mg once weekly
0.55-0.63	8	200 mg once weekly	6	150 mg once weekly
0.64-0.77	9	225 mg once weekly	8	200 mg once weekly
0.78-0.83	10	250 mg once weekly	8	200 mg once weekly
0.84-0.89	12	300 mg once weekly	10	250 mg once weekly
0.90-1.05	13	325 mg once weekly	11	275 mg once weekly
1.06-1.25	15	375 mg once weekly	13	325 mg once weekly
1.26-1.39	18	450 mg once weekly	15	375 mg once weekly
≥1.40	20	500 mg once weekly	16	400 mg once weekly

The recommended dosage modifications of tovorafenib for adverse reactions are in Table 5.

Table 5. Recommended Dosage Modifications for Adverse Reactions

Severity of ADR*	Dosage modification†
Hemorrhage
• Intolerable Grade 2 • Any Grade 3	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib.
• First occurrence of any Grade 4	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib.
• Recurrent Grade 4	Permanently discontinue tovorafenib.
Skin toxicity, including photosensitivity
• Intolerable Grade 2 • Grade 3 or 4	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib.
Hepatotoxicity
• Grade 3 AST or ALT • Grade 3 bilirubin	Withhold tovorafenib. If improved to Grade ≤ 2 or baseline, resume as follows: • If laboratory abnormality resolves within 8 days, resume tovorafenib at the same dose. • If laboratory abnormality does not resolve within 8 days, resume tovorafenib at lower dosage.
• First occurrence of any Grade 4	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib
Recurrent Grade 4	Permanently discontinue tovorafenib.
Other adverse reactions
• Intolerable Grade 2 • Any Grade 3	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. • If not improved, consider permanent discontinuation of tovorafenib.
• First occurrence of any Grade 4	Withhold tovorafenib. • If improved to Grade 0-1, resume at lower dosage. OR • Permanently discontinue tovorafenib.
• Recurrent Grade 4	Permanently discontinue tovorafenib.
* National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. † See Table 3 and Table 4 for recommended dosage reductions.

Dosage forms and strengths

Tablets. 100 mg: orange, film-coated, oval tablets debossed with "100" on one side and "D101" on the opposite side. Each tablet contains 100 mg of tovorafenib.

For oral suspension. 25 mg/mL: white to off white powder. After reconstitution, each mL of strawberry-flavored tovorafenib suspension contains 25 mg of tovorafenib. Each bottle delivers 300 mg of tovorafenib in 12 mL.

Contraindications

None.

Warnings and precautions

Hemorrhage. Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with tovorafenib. In the pooled safety population, hemorrhagic events occurred in 37% of patients, including epistaxis in 26% and intratumoral hemorrhage in 9%. Serious events of bleeding occurred in 5% of patients, including Grade 5 tumor hemorrhage in one patient (0.6%). Tovorafenib was permanently discontinued for hemorrhage in 2% of patients. Advise patients and caregivers of the risk of hemorrhage during treatment with tovorafenib. Monitor for signs and symptoms of hemorrhage and evaluate as clinically indicated. Withhold and resume at reduced dose on improvement, or permanently discontinue based on severity.

Skin toxicity, including photosensitivity. Tovorafenib can cause rash, including maculopapular rash and photosensitivity. In the pooled safety population, rash occurred in 67% of patients treated with tovorafenib, including Grade 3 rash in 12%. Rash resulted in dose interruption in 15% of patients and dose reduction in 7% of patients. Tovorafenib was permanently discontinued due to rash in 1% of patients (n=2). In the pooled safety population, dermatitis acneiform occurred in 26% of patients treated with tovorafenib, including Grade 3 dermatitis acneiform in 0.6% of patients (n=1). Dose reduction was required in 2% of patients (n=3) due to dermatitis acneiform. Monitor for new or worsening skin reactions. Consider dermatologic consultation and initiate supportive care as clinically indicated. Withhold, reduce the dose, or permanently discontinue tovorafenib based on the severity of adverse reaction.

Photosensitivity. In the pooled safety population, photosensitivity occurred in 12% of patients treated with tovorafenib, including Grade 3 events in 0.6% of patients (n=1). Advise patients to use precautionary measures against ultraviolet exposure, such as the use of sunscreen, sunglasses, and/or protective clothing during treatment with tovorafenib. Withhold, reduce the dose, or permanently discontinue tovorafenib based on the severity of adverse reaction.

Hepatotoxicity. Tovorafenib can cause hepatotoxicity. In the pooled safety population, increased alanine aminotransferase (ALT) occurred in 42% and increased aspartate aminotransferase (AST) occurred in 74%, including Grade 3 ALT in 4% and increased AST in 2% of patients treated with tovorafenib. The median time to onset of increased ALT or AST was 14 days (range: 3 to 280 days). Increased ALT or AST leading to dose interruption occurred in 5% of patients, and dose reductions were required in 1.2% of patients. Increased bilirubin occurred in 23% of patients, including Grade 3 increased bilirubin in 0.6% of patients (n=1) treated with tovorafenib. Hyperbilirubinemia leading to dose discontinuation occurred in a single adult patient with an advanced non-CNS solid tumor.

Monitor liver function tests, including ALT, AST, and bilirubin, before initiation of tovorafenib, one month after initiation, and then every 3 months thereafter, and as clinically indicated. Withhold and resume at the same or reduced dose on improvement, or permanently discontinue tovorafenib based on the severity.

Effect on growth. Tovorafenib can cause reductions in growth velocity. In FIREFLY-1, treatment-emergent adverse effects on growth occurred in 15% of patients 18 years of age or younger, including Grade 3 events in 5% of patients. Tovorafenib was permanently discontinued for a reduction in growth velocity in 2% of patients (n=2). Growth velocity recovered after interruption of treatment with tovorafenib. Routinely monitor patient growth during treatment with tovorafenib.

Embryo-fetal toxicity. Based on findings from animal studies and its mechanism of action, tovorafenib may cause fetal harm when administered to a pregnant woman. Tovorafenib was embryo lethal in rats at doses approximately 0.8-fold the human exposure at the recommended dose based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 28 days after the last dose because tovorafenib can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.

Neurofibromatosis type 1-associated tumors. Based on nonclinical data in neurofibromatosis type 1 models without BRAF alterations, tovorafenib may promote tumor growth in patients with neurofibromatosis type 1 tumors. Confirm evidence of a BRAF alteration before initiation of treatment with tovorafenib.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hemorrhage
• Skin toxicity, including photosensitivity
• Hepatotoxicity
• Effect on growth

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in the warnings and precautions section reflects exposure to tovorafenib taken orally once weekly at a dose based on body surface area in 140 patients with relapsed or refractory pediatric low-grade glioma or advanced solid tumors harboring a RAF alteration and a flat dose of 600 mg in 32 adult patients with advanced solid tumors until disease progression or intolerable toxicity. Among 172 patients treated with tovorafenib, 86% were exposed for 6 months or longer, and 49% were exposed for 1 year or longer.

Pediatric low-grade glioma. The safety of tovorafenib was evaluated in 137 patients with relapsed or refractory pediatric low-grade glioma harboring a BRAF alteration in FIREFLY-1 (Arms 1 and 2). Patients received tovorafenib at a dose based on body surface area orally once weekly until disease progression or intolerable toxicity.

The median age of patients was 9 years (range 1 to 24 years); 53% male; 58% White, 7% Asian, 2% Black or African American, 6% other races, 25% race was not reported; 2.9% were Hispanic or Latino; and 90% Karnofsky/Lansky performance status of 80 to 100.

Serious adverse reactions occurred in 45% of patients who received tovorafenib. Serious adverse reactions in more than 2% of patients included viral infection (9%), pneumonia (4%), and sepsis (4%). A fatal adverse reaction of tumor hemorrhage occurred in one patient (1%).

Permanent discontinuation of tovorafenib due to an adverse reaction occurred in 7% of patients. Adverse reactions that resulted in permanent discontinuation of tovorafenib in more than one patient were tumor hemorrhage and reduction in growth velocity.

Dosage interruptions of tovorafenib due to an adverse reaction occurred in 57% of patients. Adverse reactions that required dose interruption in 5% or more of patients included rash, pyrexia, vomiting, and hemorrhage.

Dosage reductions of tovorafenib due to an adverse reaction occurred in 24% of patients. Adverse reactions that required dose reduction in 2% or more of patients included rash and fatigue.

The most common adverse reactions (≥30%) were rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.

The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased phosphate, decreased hemoglobin, increased creatine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate transferase, decreased potassium, and decreased sodium.

For the adverse reactions and laboratory abnormalities identified in FIREFLY-1 (Arms 1 and 2), see Tables 6 and 7 in the DAILYMED drug label information.

Increased creatine phosphokinase was a clinically important laboratory abnormality that worsened from baseline in patients treated with tovorafenib.

Drug interactions

Effects of other drugs on tovorafenib. Table 8 describes drug interactions where coadministration with another drug affects tovorafenib.

Table 8. Coadministration with Other Drugs that Affect the Use of Tovorafenib

Strong or moderate CYP2C8 inhibitors
Prevention or management	• Avoid coadministration of tovorafenib with a strong or moderate CYP2C8 inhibitor.
Mechanism and clinical effect(s)	• Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure based on a mechanistic understanding of its elimination, which may increase the risk of adverse reactions with tovorafenib.
Strong or moderate CYP2C8 inducers
Prevention or management	• Avoid coadministration of tovorafenib with a strong or moderate CYP2C8 inducer.
Mechanism and clinical effect(s)	• Tovorafenib is a CYP2C8 substrate. Strong or moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure based on a mechanistic understanding of its elimination, which may reduce the effectiveness of tovorafenib.

Effects of tovorafenib on other drugs. Table 9 describes drug interactions where coadministration with tovorafenib affects another drug.

Table 9. Coadministration with Tovorafenib that Affects the Use of Other Drugs

CYP3A substrates
Prevention or management	• Hormonal contraceptives. Avoid coadministration of hormonal contraceptives with tovorafenib. If coadministration is unavoidable, use an additional effective nonhormonal contraceptive method during coadministration and for 28 days after discontinuation of tovorafenib.
	• Other CYP3A substrates. Avoid coadministration of tovorafenib with certain CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. If coadministration is unavoidable, monitor patients for loss of efficacy unless otherwise recommended in the Prescribing Information for CYP3A substrates.
Mechanism and clinical effect(s)	• Tovorafenib is a CYP3A inducer.
	• Tovorafenib is predicted to decrease exposure of certain CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures, which may reduce the effectiveness of these substrates.
	• Coadministration with hormonal contraceptives (CYP3A substrate) may decrease progestin-x and ethinyl estradiol exposure, which may lead to contraceptive failure and/or an increase in breakthrough bleeding.

Use in specific populations

Pregnancy

Risk summary. Based on findings from animal studies and its mechanism of action, tovorafenib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of tovorafenib in pregnant women. Oral administration of tovorafenib to pregnant rats during the period of organogenesis resulted in embryo lethality at exposures 0.8 times the human exposure at the recommended dose based on AUC (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data.

Animal data. In an embryo-fetal development study, once-daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.

Lactation

Risk summary. There are no data on the presence of tovorafenib or its metabolites in human milk, their effects on the breastfed child, or on milk production. Due to the potential for serious adverse reactions in breastfed children from tovorafenib, advise lactating women not to breastfeed during treatment with tovorafenib and for 2 weeks following the last dose.

Females and males of reproductive potential

Tovorafenib can cause fetal harm when administered to pregnant women.

Pregnancy testing. Verify pregnancy status in females of reproductive potential before initiating tovorafenib.

Contraception.

Females. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 28 days after the last dose. Tovorafenib can render hormonal contraceptives ineffective.

Males. Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.

Infertility. Based on findings in animals, tovorafenib may impact fertility in males and females of reproductive potential. The effects on male fertility were reversible. The effects on female fertility were not reversible.

Pediatric use

The safety and effectiveness of tovorafenib in pediatric patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation have been established based on data from a multicenter, open-label, single-arm clinical trial.

The efficacy of tovorafenib was evaluated in 76 patients with relapsed or refractory pediatric low-grade glioma. The safety of tovorafenib was evaluated in 137 patients with relapsed or refractory pediatric low-grade glioma in FIREFLY-1 (Arms 1 and 2). Of these 137 patients, 2% (n=3) were 6 months to < 2 years of age, 67% (n=92) were 2 years to < 12 years of age, and 31% (n=42) were >12 years of age. C_max and AUC in pediatric patients aged 11 months to 17 years were within the range of values observed in adults given the same dose per body surface area.

The safety and effectiveness of tovorafenib in patients younger than 6 months of age have not been established.

Effect on growth. Patients with pediatric low-grade glioma treated with tovorafenib for up to 24 months showed reductions from baseline in Z-scores for height compared to age and sex-matched normative data. Among 19 patients who experienced reductions in growth velocity who had hand radiographs taken to assess bone age, there was no evidence of premature closure of the epiphyseal growth plates or advancement of bone age. Patients followed after interruption of treatment with tovorafenib showed recovery of growth and increases in Z-scores. Monitor growth routinely during treatment.

Hepatic impairment

No dose adjustment is recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1× to 1.5× ULN and any AST) hepatic impairment. Tovorafenib has not been studied in patients with moderate (bilirubin > 1.5× to 3× ULN and any AST) to severe (bilirubin > 3× ULN and any AST) hepatic impairment.

Renal impairment

No dose adjustment is recommended for patients with mild-to-moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation). Tovorafenib has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Clinical pharmacology

Mechanism of action

Tovorafenib is a Type II RAF kinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases.

Tovorafenib exhibited antitumor activity in cultured cells and xenograft tumor models harboring BRAF V600E and V600D mutations, and in a xenograft model harboring a BRAF fusion.

Pharmacodynamics

Exposure response relationships. Tovorafenib exposure is associated with a reduction in height-for-age z-scores in pediatric patients. Reduced height-for-age risk persists during treatment with tovorafenib.

Higher tovorafenib exposure is associated with increased risk of skin rash, elevated liver enzymes (AST and ALT), and elevated creatine phosphokinase.

The exposure-response relationship for overall response rate based on RAPNO-LGG (Response Assessment in Pediatric Neuro-Oncology-Low-Grade Glioma) and RANO-LGG (Response Assessment in Neuro-Oncology-Low-Grade Glioma) was not clinically significant over the dosage range of 290 to 476 mg/m² (0.76-1.25 times the approved recommended dosage).

Cardiac electrophysiology. At the recommended tovorafenib dosage of 380 mg/m² orally once weekly (not to exceed 600 mg), a mean increase in the QT interval >20 milliseconds was not observed.

Pharmacokinetics

Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated. Tovorafenib steady-state maximum concentration (C_max) is 6.9 µg/mL (23%) and the area under the concentration-time curve (AUC) is 508 µg*h/mL (31%). Time to reach a steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in a dose-proportional manner. No clinically significant tovorafenib accumulation occurs.

Absorption. Tovorafenib median (minimum, maximum) time to achieve peak plasma concentration (T_max) is 3 hours (1.5, 4 hours), following a single dose with tablets or oral suspension.

Effect of food. No clinically significant differences in tovorafenib C_max and AUC were observed following administration of tablets with a high-fat meal (approximately 859 total calories, 54% fat) compared to fasted conditions, but the T_maxwas delayed to 6.5 hours.

Distribution. Tovorafenib’s apparent volume of distribution is 60 L/m² (23%). Tovorafenib is 97.5% bound to human plasma proteins in vitro.

Elimination. Tovorafenib’s terminal half-life is approximately 56 hours (33%), and the apparent clearance is 0.7 L/h/m² (31%).

Metabolism. Tovorafenib is primarily metabolized by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9, and CYP2C19 metabolize tovorafenib to a minor extent.

Excretion. Following a single oral dose of radiolabeled tovorafenib, 65% of the total radiolabeled dose was recovered in the feces (8.6% unchanged), and 27% of the dose was recovered in the urine (0.2% unchanged).

Specific populations. No clinically significant differences of tovorafenib were observed based on age (range: 1 to 94 years), sex, race (White, Black, Asian), mild hepatic impairment [bilirubin ≤ upper limit of normal (ULN) and AST > ULN or bilirubin > 1 to 1.5× ULN and any AST], and mild-to-moderate renal impairment (eGFR) ≥ 30 mL/min/1.73 m² calculated by Schwartz equation or MDRD equation.

Drug interaction studies

Clinical studies and model-informed approaches.

CYP3A substrates. Midazolam (CYP3A4 substrate) steady-state C_max and AUC are predicted to decrease by at least 20% following coadministration with tovorafenib.

In vitro studies.

CYP450 enzymes. Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19, and CYP3A, but does not inhibit CYP1A2, CYP2B6, and CYP2D6 at clinically relevant concentrations.

Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19 at clinically relevant concentrations.

Transporter systems. Tovorafenib is not a substrate of BCRP, P-glycoprotein (P-gp), OATP1B1, and OATP1B3. Tovorafenib has not been evaluated as a substrate of OAT1, OAT3, MATE1, MATE2-K, and OCT2. Tovorafenib inhibits BCRP at clinically relevant concentrations.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenicity studies with tovorafenib have not been conducted.

Tovorafenib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Tovorafenib was not genotoxic in cultured human lymphocytes without metabolic activation. Tovorafenib induced chromosomal aberrations in cultured human lymphocytes with metabolic activation at a single concentration in vitro. Tovorafenib was not genotoxic in an in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study in rats, animals were administered tovorafenib doses of 37.5, 75, or 150 mg/kg/day orally. Female animals, paired with untreated males, were dosed for 14 days before pairing, during the mating period, and up to Gestation Day 6. Tovorafenib decreased the number of pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at all doses. The dose of 37.5 mg/kg/day is approximately 0.8-fold the human exposure at the recommended dose based on AUC.

In repeat- dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings in female rats included reversible increased thickness of the vaginal mucosa, increased size and/or numbers of corpora hemorrhagicum and hemorrhage, and nonreversible cystic follicles, decreased corpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses ≥ 50 mg/kg once every other day (approximately 0.4-fold the human exposure at the recommended dose based on AUC). In male rats, tovorafenib reduced the weights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of the testes and reduced epididymal sperm at doses ≥ 50 mg/kg once every other day (approximately 0.3-fold the human exposure at the recommended dose based on AUC).

Animal toxicology and pharmacology

In vitro, tovorafenib increased phosphorylation of ERK at clinically relevant concentrations in cells with neurofibromatosis Type 1-loss of function (NF1-LOF), suggesting activation, rather than inhibition, of the MAP kinase pathway. In a neurofibromatosis type 1 genetically engineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did not have antitumor activity, and although not statistically significant, an increase in tumor volume was noted in 2/12 mice (approximately 17%).

Clinical studies

The efficacy of tovorafenib was evaluated in a multicenter, open-label, single-arm clinical trial (FIREFLY-1; NCT04775485). Eligible patients (N=76) were required to have a relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration based on local laboratory testing. Patients were also required to have at least one measurable lesion as defined by RANO 2010 criteria. All patients had received at least one line of prior systemic therapy and had documented evidence of radiographic progression. Patients with tumors harboring additional activating molecular alteration(s) (e.g., IDH1/2 mutations, FGFR mutations, etc.) or patients with a known or suspected diagnosis of neurofibromatosis type 1 were excluded.

Patients received tovorafenib approximately 420 mg/m² orally once weekly (range: 290 to 476 mg/m², 0.76-1.25 times the approved recommended dosage) according to body surface area, with a maximum dose of 600 mg until disease progression or unacceptable toxicity. Although the tovorafenib dosages administered in FIREFLY-1 were between 290 mg/m² to 476 mg/m², the recommended tovorafenib dosage is 380 mg/m² orally once weekly because this dosage was determined to be safe and effective for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.

Tumor assessments were performed every 12 weeks.

The major efficacy outcome measure was overall response rate, defined as the proportion of patients with complete response, partial response, or minor response by independent review based on RAPNO-LGG (Response Assessment in Pediatric Neuro-Oncology-Low-Grade Glioma) criteria. Additional efficacy outcome measures were duration of response, time to response, and overall response rate by independent review based on RANO-LGG (2011) criteria.

The efficacy population included 76 patients who had measurable disease at baseline and who received tovorafenib. The median age was 8.5 years (range 2 to 21 years); 53% were male; 53% White, 7% Asian, 2.6% Black or African American, 3.9% multiple races, 8% other race, 26% where race was not reported; 3.9% were Hispanic or Latino, and 93% had Karnofsky/Lansky performance status of 80 to 100. Patients received a median of three prior systemic regimens (range: 1 to 9). Forty-five patients (59%) received prior treatment with a MAP kinase pathway inhibitor. The most common tumor locations were the optic pathway (51%), deep midline structures (12%), brain stem (8%), cerebral hemisphere and cerebellum (7% each). Fifty-six patients (74%) had a KIAA1549:BRAF fusion, twelve patients (16%) had a V600E mutation, and eight patients (11%) had a BRAF alteration classified as "other" including BRAF duplication or BRAF rearrangement. Efficacy results are shown in Table 10.

Table 10. Efficacy Results Based on Independent Review in FIREFLY-1 (Arm-1)

Efficacy parameter	*RAPNO-LGG (N=76)**
Overall response rate
Overall response rate (95% CI)†	51% (40, 63)
Complete response, n (%)	0 (0)
Partial response, n (%)	28 (37)
Minor response, n (%)	11 (14)
Duration of response (DoR)	N=39
Median (95% CI)‡, Months	13.8 (11.3, NE)
% with observed DoR ≥ 6 months	85%
% with observed DoR ≥ 12 months	23%
Abbreviations: LGG = low-grade glioma; RAPNO = Response Assessment in Pediatric Neuro-Oncology; CI = confidence interval; NE = not estimable. * At least one measurable lesion at baseline based on RAPNO-LGG criteria. † Based on Clopper-Pearson exact confidence interval. ‡ Based on Kaplan-Meier estimate.

Among responders, the median time to response was 5.3 months (range 1.6, 11.2). In exploratory analyses of BRAF alteration status, the overall response rate was 52% among patients with BRAF fusion or rearrangement (n=64), and 50% among patients with BRAF V600E mutation (n=12), respectively. In exploratory analyses of prior therapies, the overall response rate was 49% among patients who had received prior MAPK-targeted therapy (n=45), and 55% among patients who had not received prior MAPK-targeted therapy (n=31).

Based on RANO-LGG (2011) criteria (n=76), the overall response rate was 53% (95% CI: [41, 64]), including 20 patients each with partial response and minor response, respectively.

How supplied/storage and handling

Tovorafenib tablets.

100 mg: orange, film-coated, oval tablets debossed with "100" on one side and "D101" on the opposite side and supplied as follows:

Four blister cards (four tablets each) per box, NDC 82950-001-16.

Four blister cards (five tablets each) per box, NDC 82950-001-20.

Four blister cards (six tablets each) per box, NDC 82950-001-24.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Dispense product in the original package. Tablets should not be removed from blisters until immediately before use.

Tovorafenib for oral suspension.

25 mg/mL: white to off white powder in a clear glass bottle, co-packaged with a press-in bottle adaptor and a 20 mL oral dosing syringe (NDC# 82950-012-01).

Each mL of reconstituted, strawberry-flavored tovorafenib suspension contains 25 mg of tovorafenib. Each bottle delivers 300 mg of tovorafenib in 12 mL.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Do not use if safety seal under cap is broken or missing.

Suspension must be used immediately after reconstitution.

Discard the bottle (including any unused portion) and syringe after dosing.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling.

Hemorrhage. Advise patients that tovorafenib can cause bleeding and to contact their healthcare provider for signs or symptoms of bleeding.

Skin toxicities. Advise patients that tovorafenib can cause skin toxicities and to contact their healthcare provider for worsening or intolerable rash.

Photosensitivity. Advise patients that tovorafenib can cause photosensitivity. Advise patients to limit direct ultraviolet exposure during treatment with tovorafenib. Recommend that patients use precautionary measures, such as the use of sunscreen, sunglasses, and/or protective clothing, during treatment with tovorafenib.

Hepatotoxicity. Advise patients that tovorafenib can cause liver toxicity and to contact their healthcare provider for signs or symptoms of liver dysfunction. Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with tovorafenib.

Effect on growth. Advise patients and caregivers that treatment with tovorafenib may cause a reduction in growth velocity, and that growth will be monitored during treatment with tovorafenib.

Embryo-fetal toxicity.

	• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
	• Advise females to inform their healthcare provider of a known or suspected pregnancy during treatment with tovorafenib.
	• Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 28 days after discontinuation of treatment with tovorafenib.
	• Advise male patients with female partners of reproductive potential to use effective nonhormonal contraception during treatment with tovorafenib and for 2 weeks after the last dose.

Lactation. Advise women not to breastfeed during treatment with tovorafenib and for 2 weeks after the last dose of tovorafenib.

Infertility. Advise males and females of reproductive potential of the potential risk for impaired fertility with tovorafenib.

Dosing and administration. Inform patients and caregivers on how to take tovorafenib and what to do for missed or vomited doses.

Before use of the oral suspension, ensure patients or caregivers receive training on proper dosing, preparation, and administration.

Storage. Advise patients not to take the tovorafenib tablets out of the blister pack until ready to use.